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Tumors with TSC mutations are sensitive to CDK7 inhibition through NRF2 and glutathione depletion.
Journal of Experimental Medicine ( IF 12.6 ) Pub Date : 2019-09-10 , DOI: 10.1084/jem.20190251 Mahsa Zarei 1, 2 , Heng Du 1 , Amin H Nassar 1 , Rachel E Yan 1 , Krinio Giannikou 1 , Sneha H Johnson 2 , Hilaire C Lam 3 , Elizabeth P Henske 3 , Yubao Wang 4 , Tinghu Zhang 4, 5 , John Asara 6 , David J Kwiatkowski 7
Journal of Experimental Medicine ( IF 12.6 ) Pub Date : 2019-09-10 , DOI: 10.1084/jem.20190251 Mahsa Zarei 1, 2 , Heng Du 1 , Amin H Nassar 1 , Rachel E Yan 1 , Krinio Giannikou 1 , Sneha H Johnson 2 , Hilaire C Lam 3 , Elizabeth P Henske 3 , Yubao Wang 4 , Tinghu Zhang 4, 5 , John Asara 6 , David J Kwiatkowski 7
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Tuberous sclerosis complex (TSC) is characterized by tumor development in the brain, heart, kidney, and lungs. In TSC tumors, loss of the TSC1/TSC2 protein complex leads to activation of mTORC1 with downstream effects on anabolism and cell growth. Because mTORC1 activation enhances mRNA transcription, we hypothesized that aberrant mTORC1 activation might confer TSC-null cell dependence on transcriptional regulation. We demonstrate that TSC1- or TSC2-null cells, in contrast to their wild-type counterparts, are sensitive to pharmacological inhibition of CDK7. Mechanistic studies revealed that CDK7 inhibition markedly reduces glutathione levels and increases reactive oxygen species due to reduced expression of NRF2 and glutathione biosynthesis genes. Treatment of both Tsc2+/ - mice and a TSC1-null bladder cancer xenograft model with a CDK7 inhibitor showed marked reduction in tumor volume and absence of regrowth in the xenograft model. These results suggest that CDK7 inhibition is a promising therapeutic approach for treatment of TSC-associated tumors and cancers with mutations in either TSC1 or TSC2.
中文翻译：
具有TSC突变的肿瘤通过NRF2和谷胱甘肽耗竭对CDK7抑制敏感。
结节性硬化症（TSC）的特征是大脑，心脏，肾脏和肺部的肿瘤发展。在TSC肿瘤中，TSC1 / TSC2蛋白复合物的缺失会导致mTORC1的激活，并对合成代谢和细胞生长产生下游影响。因为mTORC1激活增强了mRNA的转录，我们假设异常的mTORC1激活可能赋予TSC空细胞依赖转录调控。我们证明TSC1或TSC2空细胞，与其野生型对应物相比，对CDK7的药理抑制敏感。机理研究表明，由于NRF2和谷胱甘肽生物合成基因的表达减少，CDK7抑制作用显着降低了谷胱甘肽水平并增加了活性氧。用CDK7抑制剂治疗Tsc2 +/-小鼠和TSC1无效的膀胱癌异种移植模型均显示出肿瘤体积显着减少，异种移植模型中没有再生长。这些结果表明，CDK7抑制是治疗TSC相关肿瘤和TSC1或TSC2突变的癌症的有前途的治疗方法。
更新日期：2019-11-04
中文翻译：
具有TSC突变的肿瘤通过NRF2和谷胱甘肽耗竭对CDK7抑制敏感。
结节性硬化症（TSC）的特征是大脑，心脏，肾脏和肺部的肿瘤发展。在TSC肿瘤中，TSC1 / TSC2蛋白复合物的缺失会导致mTORC1的激活，并对合成代谢和细胞生长产生下游影响。因为mTORC1激活增强了mRNA的转录，我们假设异常的mTORC1激活可能赋予TSC空细胞依赖转录调控。我们证明TSC1或TSC2空细胞，与其野生型对应物相比，对CDK7的药理抑制敏感。机理研究表明，由于NRF2和谷胱甘肽生物合成基因的表达减少，CDK7抑制作用显着降低了谷胱甘肽水平并增加了活性氧。用CDK7抑制剂治疗Tsc2 +/-小鼠和TSC1无效的膀胱癌异种移植模型均显示出肿瘤体积显着减少，异种移植模型中没有再生长。这些结果表明，CDK7抑制是治疗TSC相关肿瘤和TSC1或TSC2突变的癌症的有前途的治疗方法。
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